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ASEAN VARIATION GUIDELINE FOR PHARMACEUTICAL PRODUCTS

FINAL DRAFT 7.2

2013

ASEAN Variation Guideline for Pharmaceutical Products 2013(Final Draft 7.2)

i

LIST OF CONTENTS Page

1 INTRODUCTION 1

2 SCOPE OF THIS GUIDELINE 1

3 DEFINITION 1

3.1 Major Variation (MaV) 1

3.2 Minor Variation (MiV-PA & MiV-N) 1

4 PROCEDURE AND TIMELINE 2-3

5 CHANGES LEADING TO A NEW PRODUCT REGISTRATION 3

6 OTHERS 3

7 MAJOR VARIATION (MaV)

MaV-1 Change and/or additional indication/dosing regimen/patient population/inclusion of clinical information extending the usage of the product

4

MaV-2 Change of content of product labeling 4

MaV-3 Change and/or addition of alternative manufacturer/site of drug substance [where European Pharmacopoeial Certificate of Suitability (CEP) is not available]

5

MaV-4 Addition or replacement of the manufacturing site of the drug product

6

MaV-5 Addition or replacement of the alternative site for the primary packaging (direct contact with drug product)

7

MaV-6 Change of the specification drug substance and/or drug product [where European Pharmacopoeial Certificate of Suitability (CEP) is not available]

8

MaV-7 Change of batch size of sterile drug product 9

MaV-8 Change of batch size of non-sterile drug product 10

MaV-9 Major change in the manufacturing process for the drug product 11

MaV-10 Qualitative or quantitative change of excipient 12

MaV-11 Quantitative change in the coating weight of tablets or weight and/or size of capsule shell for modified release oral dosage form

13

MaV-12 Change in primary packaging material for sterile product a) Qualitative and quantitative composition and/or b) Type of container and/or c) Inclusion of primary packaging material

14

MaV-13 Change or addition of pack size/fill volume and/or change of shape or dimension of container or closure for sterile solid and liquid drug product

15

MaV-14 Inclusion or replacement of the solvent/diluent for the drug product 15

MaV-15 Extension of shelf-life of the drug product 16

MaV-16 Change of storage conditions of the drug product (Lowering from the current approved storage condition)

16

8 MINOR VARIATION PRIOR APPROVAL (MiV-PA)

MiV-PA1 Change of drug product name 17

MiV-PA2 Change of product labeling (in accordance to country specific labeling requirement)

17


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MiV-PA3 Addition or replacement of the company or party responsible for batch release

18

MiV-PA4 Change and/or addition of alternative manufacturer/site of drug substance [where European Pharmacopoeial Certificate of Suitability (CEP) is available]

18

MiV-PA5 Change of batch size of drug substance [where European Pharmacopoeial Certificate of Suitability (CEP) is not available]

19

MiV-PA6 Change of in-process controls applied during the manufacture of the drug substance [including tightening and addition of new in-process test and where European Pharmacopoeial Certificate of Suitability (CEP) is not available]

19

MiV-PA7 Change of manufacturing process of the drug substance [where European Pharmacopoeial Certificate of Suitability (CEP) is not available]

20

MiV-PA8 Change of the specification of drug substance 21

MiV-PA9 Change of the test procedure of non-compendial drug substance 21

MiV-PA10 Change of shelf-life or retest period for drug substance 22

MiV-PA11 Change of storage condition for drug substance 22

MiV-PA12 Revision of European Pharmacopoeial Certificate of Suitability (CEP) of drug substance

22

MiV-PA13 Change of batch size of non-sterile drug product 23

MiV-PA14 Reduction or removal of overage 23

MiV-PA15 Qualitative or quantitative change of excipient 24

MiV-PA16 Quantitative change in coating weight of tablets or weight and/or size of capsule shell for immediate release oral dosage form

25

MiV-PA17 Change of the colouring/flavouring agent of the product [addition, deletion or replacement of colourant(s)/flavour(s)]

26

MiV-PA18 Deletion of the solvent/diluent for the drug product 26

MiV-PA19 Change of in-process controls applied during the manufacture of the drug product (including tightening and addition of new in-process test)

27

MiV-PA20 Minor change of the manufacturing process for non-sterile product 28

MiV-PA21 Change of specifications of an excipient 29

MiV-PA22 Change of a test procedure for an excipient, including replacement of an approved test procedure by a new test procedure

29

MiV-PA23 Change in the source of empty hard capsule 30

MiV-PA24 Change of release and shelf-life specifications of the drug product 30

MiV-PA25 Change of imprints, bossing or other markings on the tablets or printing on capsules including addition or change of inks used for product marking

31

MiV-PA26 Change of dimensions and/or shape of tablets, capsules, suppositories or pessaries without change in qualitative and quantitative composition and mean mass

32

MiV-PA27 Change in the test procedure of the drug product (including replacement or addition of a test procedure)

33

MiV-PA28 Change in primary packaging material for non-sterile product a) Qualitative and quantitative composition and/or b) Type of container and/or c) Inclusion of primary packaging material

33


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MiV-PA29 Addition or replacement of a manufacturer for secondary packaging

34

MiV-PA30 Change of pack size/fill volume and/or change of shape or dimension of container or closure for non-sterile product

34

MiV-PA31 Change of outer carton pack sizes for a drug product 35

MiV-PA32 Change in any part of the (primary) packaging material not in contact with the finished product formulation (such as colour of flip-off caps, colour code rings on ampoules, change of needle shield (different plastic used)

35

MiV-PA33 Addition or replacement of measuring device for oral liquid dosage forms and other dosage form

35

MiV-PA34 Reduction of shelf-life of the drug product

36

MiV-PA35 Change of storage conditions of the drug product (Increasing from the current approved storage condition)

36

9 MINOR VARIATION NOTIFICATION (MiV-N)

MiV-N1 Change in name and/or address of the marketing authorization holder

37

MiV-N2 Change of product owner 37

MiV-N3 Change in ownership of manufacturer 38

MiV-N4 Change of the name or address (for example: postal code, street name) of the manufacturer of drug product

38

MiV-N5 Change of the name or address (for example: postal code, street name) of the company or manufacturer responsible for batch release

39

MiV-N6 Change of the name and/or address (for example: postal code, street name) of a manufacturer of the drug substance

39

MiV-N7 Withdrawal/deletion of the alternative manufacturer(s) (for drug substance and/or drug product and/or packager)

39

MiV-N8 Renewal of European Pharmacopoeial Certificate of Suitability (CEP)

40

MiV-N9 Change of release and shelf-life specifications of the drug product and/or drug substance and/or excipient, following the updates in the compendium

40

MiV-N10 Deletion of pack size for a product 40

10 GLOSSARY 41

11 REFERENCES 41


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ASEAN VARIATION GUIDELINE FOR PHARMACEUTICAL PRODUCTS 1. INTRODUCTION Throughout the life of a pharmaceutical product, the marketing authorization holder is responsible for the product that is placed in the market and is also required to take into account technical and scientific progress, and to make any amendments that may be required to enable the pharmaceutical products to be manufactured and checked by means of generally accepted scientific methods. Such amendments have to be approved by the Drug Regulatory Authority. This guidance document is intended to provide supportive information on the requirements for submission of a variation application to implement a change to a pharmaceutical product. Variation applications are categorized into major variation, minor variation (prior approval) and minor variation (notification). Updating of this guideline will be done on a periodic basis as required. 2. SCOPE OF THIS GUIDELINE This ASEAN Variation Guideline concerns the variation applications submitted by the marketing authorization holder for pharmaceutical products for human use only and not including biologics. 3. DEFINITION 3.1 Major variation (MaV) Variation to a registered pharmaceutical finished product that may affect significantly and/or directly the aspects of quality, safety and efficacy and it does not fall within the definition of minor variation and new registration. 3.2 Minor Variation (MiV-N & MiV-PA) Variation to a registered pharmaceutical finished product in terms of administrative data and/or changes with minimal/no significant impact on the aspects of efficacy, quality, and safety.


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4. PROCEDURE AND TIMELINE Variation application is submitted along with a declaration letter undersigned by the Head of Regulatory Officer that declares there is no other change except for the proposed variation

4.1 Minor Variation – Notification

Type of variation

Minor variation (Notification)

MiV-N

Procedure

Notification “Do & Tell”

If the notification fulfils the requirements (conditions and supporting documents) as per described under MiV-N, the Drug Regulatory Authority shall acknowledge receipt of a valid

notification.

Timeline for the Drug Regulatory Authority to

acknowledge the variation notification

Within a duration subject to country specific proposal, following receipt of a valid notification.

4.2 Minor Variation –Prior Approval and Major Variation

Type of variation Minor variation (Prior approval)

MiV-PA

Major variation MaV

Procedure

Prior approval

If the application fulfils the requirements (conditions

and supporting documents) as per

described under MiV-PA, the Drug Regulatory

Authority shall issue an approval for the proposed

change.

Prior approval

If the application fulfils the requirements (conditions

and supporting documents) as per

described under MaV, the Drug Regulatory Authority shall issue an approval for

the proposed change.

Timeline for the Drug Regulatory Authority to evaluate the variation

application

Within a duration subject to country specific proposal following receipt of a valid

application.

Within a duration subject to country specific proposal following receipt of a valid

application.


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Implementation of the variation

Within a duration subject to country specific proposal after the marketing authorization holder has been

informed of the approved variations.

Note: 1. The ‘timeline’ and ‘implementation of the variation’ is subject to country specific

proposals and be made publicly available. 2. The Drug Regulatory Authority reserves the right to re-categorize the application

type, where deemed appropriate. Subject to country specific procedure, re-categorization may require the marketing authorization holder to withdraw the original application and resubmit a new application according to the correct category.

5. CHANGES LEADING TO A NEW PRODUCT REGISTRATION Changes requiring a new product registration may vary from country to country. Certain variations described in this guideline may require a new product registration in certain countries. Applicants are advised to check with individual country on the applicability of this variation guideline 6. OTHERS 6.1 Lead compendium refers to British Pharmacopeia (BP), United States Pharmacopeia (USP) and European Pharmacopeia (EP). 6.2 Any variations not yet listed in this guideline should be justified and decided by the Drug Regulatory Authority. Appropriate reference can be made to:

i. EMA Classification Guidance On Minor Variations of Type IA, Minor Variations of Type IB And Major Variations of Type II.

ii. SUPAC-IR: Immediate-Release Solid Oral Dosage Forms: Scale-Up And Post-Approval Changes: Chemistry, Manufacturing And Controls, In Vitro Dissolution Testing, And In Vivo Bioequivalence Documentation.

iii. SUPAC-MR: Modified Release Solid, Oral Dosage Forms, Scale-Up and Postapproval Changes: Chemistry, Manufacturing, and Controls; In Vitro Dissolution Testing and In Vivo Bioequivalence Documentation.

iv. WHO Guidance On Variations To A Prequalified Product Dossier.

6.3 The Drug Regulatory Authority reserves the right to request for additional information, when deemed necessary. 6.4 Abbreviations: C = Conditions to be fulfilled D = Documents to be submitted MaV = Major Variation MiV-N = Minor Variation (Notification) MiV-PA = Minor Variation (Prior Approval)


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7. MAJOR VARIATION

Major Variation (MaV)

MaV- 1

Change and/or additional indication/dosing regimen/patient population/inclusion of clinical information extending the usage of the product

C

1. Product labeling refers to Package Insert (PI), Patient Information Leaflet (PIL),

unit carton label, inner label and/or blister strips. 2. As a subsequent change due to revision of Summary of Product

Characteristics (SmPC) or equivalent document (USPI).

D

1. Currently approved product labeling. 2. Proposed product labeling, a clean and annotated version highlighting the

changes made. 3. Approved PI/SmPC/PIL from an approved reference regulatory agency or the

country of origin containing the proposed changes (where applicable). 4. Justifications for the changes proposed. 5. Approval letters from reference countries or country of origin which have

approved the new indication or dosing regimen (where applicable). 6. Clinical expert reports and/or clinical trial reports (where applicable). 7. Clinical documents as per ASEAN Common Technical Dossier (ACTD) part IV

(where applicable).

MaV-2 Change of content of product labeling

C


unit carton label, inner label and/or blister strips. 2. The change is not a minor variation and not within the scope of MaV-1. 3. As a subsequent change due to revision of Summary of Product

Characteristics (SmPC) or equivalent document (USPI).

D

1. Currently approved product labeling. 2. Proposed product labeling, a clean and annotated version highlighting the

changes made. 3. Approved PI/SmPC/PIL from an approved reference regulatory agency or the

country of origin containing the proposed changes (where applicable). 4. Justifications for the changes proposed and supporting clinical documents

when applicable.


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MaV-3

Change and/or addition of alternative manufacturer/site of drug substance [where European Pharmacopoeial Certificate of Suitability (CEP) is not available]

C

1. Specifications of drug substances remain unchanged. 2. For Change and/or addition of alternative manufacturer/site of drug substance

where European Pharmacopoeial Certificate of Suitability (CEP) is available, please refer to MiV-PA4.

D

1. Complete ACTD section S1-S7, or both the open and closed part of the Drug

Master File (closed part may be provided directly by manufacturer) with the Letter of Access or equivalent audit document/certification from reference country which is deemed appropriate by the Drug Regulatory Authority.

2. Comparative tabulated format of the currently registered and revised drug substance manufacture information (where applicable).

3. Batch analysis data (in a comparative tabular format) for at least two pilot batches of the drug substance from the current and proposed manufacturing sites.

4. A letter of commitment from marketing authorization holder to conduct real time and accelerated stability studies for the drug product manufactured with the drug substance from the proposed manufacturing site, and report if any results fall outside shelf-life specifications (with proposed action) or when requested.


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MaV-4 Addition or replacement of the manufacturing site of the drug product

C

1. Not applicable to changes relating to manufacturer responsible for batch

release or a site where only batch release takes place. 2. For addition or replacement of the company or party responsible for batch

release, please refer to MiV-PA3. 3. If there are changes to the manufacturing process, MaV-9 is also applicable.

D

1. Revised drafts of the package insert and labeling incorporating the proposed

variation (where applicable). 2. Proof that the proposed site is appropriately authorized for the pharmaceutical

form concerned such as a valid Good Manufacturing Practice (GMP) certificate and/or a Certificate of Pharmaceutical Product (CPP) which covers GMP certification.

3. Batch numbering system (where applicable). 4. In case of a contract manufacturer, letter of appointment and letter of

acceptance for the proposed site to manufacture the product and stating the types of activity to be performed (where applicable).

5. Specification of drug substance. 6. Product formula. 7. Comparative dissolution profile data manufactured in the currently approved

and proposed manufacturing site for oral solid dosage forms as per compendium and validated dissolution test method.

8. Validation scheme and/or report of the manufacturing process as per ASEAN Guideline on Submission of Manufacturing Process Validation Data for Drug Registration at the proposed site should be provided upon submission.

9. Holding time studies testing of bulk pack during storage and transportation between the bulk production site and primary packager (where applicable).

10. Release and shelf-life specifications of drug product. 11. Comparative batch analysis data of drug product of at least two production

batches (or one production batch and two pilot batch) from the proposed site and last three batches from the current site; batch analysis data on the next two full production batches should be available upon request or reported if outside specifications (with proposed action).

12. Stability data as per ASEAN Guideline On Stability Study Of Drug Product and report if any results fall outside shelf-life specifications (with proposed action).


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MaV-5 Addition or replacement of alternative site for primary packaging (direct contact with drug product)

C

1. No other changes except for the addition or replacement of alternative site for

primary packaging (direct contact with drug product).

D


variation (where applicable). 2. Proof that the proposed site is appropriately authorized for the packaging

activity of the pharmaceutical form concerned such as a valid GMP Certificate and/or a CPP which covers GMP certification.

3. In case of a contract primary packager, letter of appointment and letter of acceptance for the proposed site to package the product and stating the types of activity to be performed by the packager (where applicable).

4. For sterile product, validation scheme and/or report on primary packaging processes as per ASEAN Guideline on Submission of Manufacturing Process Validation Data for Drug Registration at the proposed site should be provided upon submission.

5. Holding time studies testing of bulk pack during storage and transportation between the bulk production site to primary packager (where applicable).



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MaV-6

Change of the specification of drug substance and/or drug product [where European Pharmacopoeial Certificate of Suitability (CEP) is not available]

a) Specification limits are widened b) Deletion of test parameter and limits

C

1. Test procedures remain the same, or changes in the test procedure are minor. 2. Not applicable to compendial drug substances/drug products. 3. The change should not be the result of unexpected events arising during

manufacture or because of stability concerns. 4. Refer to MiV-PA12 if this change resulted in revision of CEP.

D

(a) Specification limits are widened 1. Revised specification of drug substance / drug product. 2. Comparative tabulated format of the currently approved and revised

specification of drug substance/drug product with changes highlighted. 3. Batch analysis data of the drug substance/drug product for all tests in the new

specification for two pilot or production scale batches. 4. Justification for change substantiated with scientific data to be provided. 5. Stability data as per ASEAN Guideline On Stability Study Of Drug Product and

report if any results fall outside shelf-life specifications (with proposed action).

(b) Deletion of test parameter and limits In addition to the above documents except D5, 6. Certificate of analysis of the drug substance/drug product for all tests with the

new specification.


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MaV-7 Change of batch size of sterile drug product

C

1. The change does not affect consistency of production. 2. The product formulation remains unchanged. 3. Release and shelf-life specifications of drug product remain unchanged. 4. Process validation scheme and/or report is available or validation of the

manufacturing process has been successfully carried out according to protocol with at least three batches appropriate to the proposed batch size in accordance with the ASEAN Guideline on Submission of Manufacturing Process Validation Data For Drug Registration.

D

1. Comparative tabulated format of proposed and currently approved batch

manufacturing formula. 2. Validation scheme and/or report of the manufacturing process as per ASEAN

Guideline on Submission of Manufacturing Process Validation Data for Drug Registration of the proposed batch size should be provided upon submission.

3. Release and shelf-life specifications of the drug product. 4. Batch analysis data (in a comparative tabulated format) of drug product of at

least two production batches manufactured according to currently approved and proposed batch sizes.



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MaV-8 Change of batch size of non-sterile drug product

C

1. The change does not affect consistency of production. 2. Release and shelf-life specifications of drug product remain unchanged. 3. Process validation scheme and/or report is available or validation of the

manufacturing process has been successfully carried out according to protocol with at least three batches appropriate to the proposed batch size in accordance with the ASEAN Guideline on Submission of Manufacturing Process Validation Data For Drug Registration.

4. This is applicable to change of batch size more than 10-fold compared to the currently registered batch size. For change of batch size up to 10-fold compared to the currently registered batch size, please refer MiV-PA13.

D

1. For oral solid dosage forms, comparative dissolution profile for at least one

production batch (where applicable). 2. Comparative tabulated format of proposed and current batch manufacturing

formula. 3. Validation scheme and/or report of the manufacturing process as per ASEAN

Guideline on Submission of Manufacturing Process Validation Data for Drug Registration the proposed batch size should be provided upon submission.

4. Release and shelf-life specifications of the drug product. 5. Batch analysis data (in a comparative tabulated format) of drug product on a

minimum of one production batch manufactured according to currently approved and proposed batch sizes and letter of undertaking to submit batch data on the next one full production batch.



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MaV-9 Major change in the manufacturing process for drug product

C

1. The change does not cause a negative impact on the quality, safety and

efficacy of the drug product. 2. The same currently approved manufacturing site. If there is a change in

manufacturing site, MaV-4 is also applicable. 3. For minor change of the manufacturing process for non-sterile product, please

refer to MiV-PA20.

D

1. Description of the new manufacturing process and technical justification for the

change. 2. Comparative dissolution profile data between the products manufactured with

the currently approved and proposed manufacturing process for oral solid dosage forms as per compendium and validated dissolution test method.

3. Validation scheme and/or report of the proposed manufacturing process as per ASEAN Guideline on Submission of Manufacturing Process Validation Data for Drug Registration should be provided upon submission.

4. Copy of currently approved release and shelf-life specifications. Or, alternatively, copy of proposed release and shelf-life specifications that supports that the new process must lead to an identical or better product regarding all aspects of quality, safety and efficacy.

5. Comparative batch analysis data of drug product for a minimum of one production batch manufactured according to currently registered and proposed processes.


7. Justification for not submitting a new bioequivalence study according to ASEAN Guidelines for the Conduct of Bioavailability and Bioequivalence Studies (where applicable).


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MaV-10

Qualitative or quantitative change of excipient a) For immediate release oral dosage forms

(as per Level 2 and 3, Part III Components and Composition, SUPAC guideline)

b) For modified release oral dosage forms c) For other critical dosage forms such as sterile preparations.

C

1. Change will need to comply with the finished product specifications for

example release and shelf-life specifications of the drug product remain the same, excluding product description.

2. Replacement of an excipient with a comparable excipient of the same functional characteristics.

3. The dissolution profile of the proposed product is comparable to that of the current approved product.

4. Process validation scheme and/or report is available or validation of the manufacturing process has been successfully carried out according to protocol with at least three batches of the proposed new product formula in accordance with the ASEAN Guideline on Submission of Manufacturing Process Validation Data For Drug Registration.

5. For other qualitative or quantitative changes of excipient for immediate release oral dosage forms and other non-critical dosage forms, please refer to MiV-PA15.

D


variation (where applicable). 2. Justification for the change must be given by appropriate development of

pharmaceutics. 3. Comparative tabulated format of the current and revised product formulation

with calculated changes highlighted (please state changes in the percentage of the proposed excipient out of the total target dosage form weight, where applicable).

4. Comparative dissolution profile data of at least one representative pilot/production batch of the drug product between the currently approved and proposed solid dosage forms formulation (where applicable).

5. Revised batch manufacturing formula. 6. Validation scheme and/or report of the manufacturing process as per ASEAN

Guideline on Submission of Manufacturing Process Validation Data for Drug Registration appropriate to the proposed change in product formula should be provided upon submission.

7. Revised ACTD Section P3.1 to P3.4 (where applicable). 8. Specifications of the proposed excipient. 9. For proposed excipients made of ruminants source, Transmitting Animal

Spongiform Encephalopathy (TSE)-free certificate or Bovine Spongiform Encephalopathy (BSE)-free cert issued from relevant veterinary authority of the issuing country (where applicable).

10. Drug product release and shelf-life specifications. 11. Batch analysis data (in a comparative tabulated format) of drug product on at

least two production (or one production batch and two pilot batches) according to currently approved and proposed product formula.


13. Justification for not submitting a new bioequivalence study according to ASEAN Guidelines for the Conduct of Bioavailability and Bioequivalence Studies (where applicable).


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MaV-11 Quantitative change in coating weight of tablets or weight and/or size of capsule shell for modified release oral dosage form

C

1. The dissolution profile of the proposed product is comparable to that of the

current approved product. 2. The release and shelf-life specifications of the drug product remain unchanged

except for the weight and/or size (where applicable). 3. For quantitative change in coating weight of tablets or weight and/or size of

capsule shell for immediate release oral solid dosage forms, please refer to MiV-PA16.

D

1. Revised draft of product label incorporating the proposed change (where

applicable). 2. A declaration that the change does not interfere with the drug product release

and shelf-life specifications test method. 3. Comparative dissolution profile data of at least one pilot/production batch of

the drug product between the currently approved and proposed composition. 4. Current and proposed product and batch manufacturing formula. 5. Revised release and shelf-life specifications of the drug product. 6. Stability data as per ASEAN Guideline On Stability Study Of Drug Product and

report if any results fall outside shelf-life specifications (with proposed action). 7. Justification for not submitting a new bioequivalence study according to the

ASEAN Guidelines For The Conduct of Bioavailability and Bioequivalence Studies (where applicable).


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MaV-12

Change in primary packaging material for sterile product a) Qualitative and quantitative composition and/or b) Type of container and/or c) Inclusion of primary packaging material

C

1. Release and shelf-life specifications of the drug product remain unchanged. 2. For change in the primary packaging material for non-sterile drug product,

please refer to MiV-PA28.

D


variation (where applicable). 2. Appropriate scientific data on new packaging (comparative data on

permeability, e.g. moisture, O2, CO2). 3. Proof must be provided that no interaction between the content and the

packaging material occurs (where applicable). 4. Validation scheme and/or report of the manufacturing and sterilization process

as per ASEAN Guideline on Submission of Manufacturing Process Validation Data for Drug Registration appropriate to the proposed change in primary packaging material should be provided upon submission.

5. Comparative tabulated format of specifications of the proposed and current primary packaging material.

6. Revised ACTD Sections P3 and/or P7 (where applicable). 7. Stability data as per ASEAN Guideline On Stability Study Of Drug Product and



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MaV-13

Change or addition of pack size/fill volume and/or change of shape or dimension of container or closure for sterile solid and liquid drug product

C

1. The proposed pack size is consistent with the dosage regimen and duration of

use as approved in the package insert. 2. The packaging material remains the same. 3. Release and shelf-life specifications of the drug product are not affected,

except pack size/fill volume specification. 4. Change or addition of pack size/fill volume and/or change of shape or

dimension of container or closure for non-sterile drug product, please refer to MiV-PA30.

D


variation (where applicable). 2. Justification that the proposed pack size is consistent with the dosage regimen

and duration of use as approved in the package insert. 3. Validation data of the manufacturing process, sterilization and container

closure system (where applicable). 4. Stability data as per ASEAN Guideline On Stability Study Of Drug Product and


MaV-14 Inclusion or replacement of the solvent/diluent for the drug product

C

1. The proposed change does not result in any change in the dosage form,

regimen, indication, method of administration of the product. 2. For deletion of the solvent/diluent, please refer to MiV-PA18. 3. For change of shelf-life and/or storage condition of the drug product after first

opening and/or after dilution/reconstitution, please also refer to MaV-15/MiV-PA34 and/or MaV-16/MiV-PA35 (where applicable)

D


variation. 2. Documentary evidence to certify the manufacturing site of diluents/solvents

complies with current applicable GMP standards (where applicable). 3. Batch numbering system (where applicable). 4. A letter of authorization from product owner to authorize the manufacturing site

to manufacture and package the solvent/diluent (where applicable). 5. A declaration from the marketing authorization holder that the release and

shelf-life specifications of drug product are not affected. 6. In addition to section P for the solvent/diluent and reconstitution stability data,

section S is also required (where applicable).


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MaV-15

Extension of shelf-life of the drug product a) As a package for sale and/or b) After first opening and/or c) After dilution/reconstitution

C

1. For (a) & (b) - The studies must show conformance to the currently approved

shelf-life specification. 2. For (c)–The studies must show conformance to the currently approved shelf-

life specification for the reconstituted product. 3. For reduction of shelf-life, please refer to MiV-PA34.

D


variation (where applicable). 2. Justification letter for the change of shelf-life of the drug product (where

applicable). 3. A letter of commitment from product owner or marketing authorization holder to

inform users of the relevant change (where applicable). 4. Results of appropriate real time stability studies covering the duration of

proposed shelf-life of at least two pilot/production scale batches of the product in the authorized packaging material a) as a package for sale and/or b) after first opening and/or c) after the dilution/reconstitution in accordance with the ASEAN Guidelines on Stability Study of Drug Product; results of appropriate microbiological testing should be included (where appropriate).

MaV-16

Change of storage conditions of the drug product (Lowering from the current approved storage condition)

a) As a package for sale and/or b) After first opening and/or c) After dilution/reconstitution

C


shelf-life specification. 2. For (c) – The studies must show conformance to the currently approved shelf-

life specification for the reconstituted product. 3. For change of storage condition (Increasing from the current approved storage

condition), please refer to MiV-PA35.

D


variation (where applicable). 2. Technical justification for the change. 3. Results of appropriate real time stability studies covering the duration of

currently approved shelf-life (at proposed storage condition) of at least two pilot/production scale batches of the product and in the authorized packaging material in accordance with the ASEAN Guidelines on Stability Study of Drug Product.


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8. MINOR VARIATIONPRIOR APPROVAL

Minor Variation (MiV-PA)

Prior Approval

MiV- PA1

Change of drug product name

C

1. There is no change to the product (formulation, release and shelf-life

specifications, manufacturing source and process) except for the product name change.

2. No confusion with another drug product either when spoken or written. 3. The new name does not (i) suggest greater safety or efficacy than supported

by clinical data (ii) imply a therapeutic use (iii) imply superiority over another similar product and (iv) imply the presence of substance(s) not present in the product.

D

1. Revised draft package insert and labeling incorporating the proposed variation. 2. Updated Certificate of Pharmaceutical Product (CPP) (where applicable). 3. Official letter from product owner or marketing authorization holder authorizing

the change of product name and committing to inform users of the relevant changes (where applicable).

4. A declaration from the marketing authorization holder that there is no other changes to the product/label except for the drug product name change.

5. Trademark certificate (where applicable).

MiV- PA2

Change of product labeling (in accordance to country specific labeling requirement) Includes:

a) Change of the layout/artwork without altering meaning. b) Addition/deletion/replacement of pictures, diagrams, bar code, logos and/or

texts that do not imply an unapproved indication. c) Addition/strengthening of warnings, precautions, contraindications and/or

adverse events/effects to the approved product labelling. d) Tightening of product’s target population. e) Deletion of indication. f) Change of distributor’s details.

C


unit carton label, inner label and/or blister strips. 2. The change is not a MaV and does not contain promotional information. For

major change in product labelling, please refer to MaV-2.

D

1. Current approved product labeling. 2. Proposed product labeling, a clean and annotated version highlighting the

changes made. 3. Letter of declaration from the marketing authorization holder stating that no

other changes on the label except for the intended change. 4. Relevant document/reference to support the changes (where applicable).


18

MiV- PA3

Addition or replacement of the company or party responsible for batch release

C

1. Only applicable for batch release. 2. The manufacturer of the drug product remains the same. 3. Method transfer from the currently approved to the proposed site or test

laboratory has been successfully completed.

D


variation (where applicable). 2. Proof that the proposed site is appropriately authorized (accredited by the

authority) to be responsible for batch release such as a valid GMP certificate or CPP which covers the GMP certification.

3. Official letter from product owner authorizing the company/manufacturer to be responsible for batch release (where applicable).

MiV- PA4

Change and/or addition of alternative manufacturer/site of drug substance [where European Pharmacopoeial Certificate of Suitability (CEP) is available]

C

1. Specifications of drug substances remain unchanged. 2. For change and/or addition of alternative manufacturer/site of drug substance

where CEP is not available, please refer to MaV-3.

D

1. A valid European Pharmacopoeial Certificate of Suitability (CEP) for the drug

substance, latest version, with all annexes issued by the European Directorate for the Quality of medicines (EDQM).

2. A letter of commitment from marketing authorization holder to conduct real time and accelerated stability studies for the drug product manufactured with the drug substance from the proposed manufacturing site, and report if any results fall outside shelf-life specifications (with proposed action) or when requested.

3. Batch analysis data (in a comparative tabular format) for at least two pilot batches of the drug substance from the current and proposed manufacturing sites.

4. If the re-test period is not stated in the CEP, real time and accelerated stability data up to the proposed re-test period on two pilot batches of the drug substance manufactured from the proposed manufacturing sites should be provided.


19

MiV- PA5

Change of batch size of drug substance [where European Pharmacopoeial Certificate of Suitability (CEP) is not available]

C

1. The change does not affect the reproducibility of the process. 2. Specifications of drug substance remain unchanged. 3. Refer to MiV-PA12 if this change resulted in revision of CEP.

D

1. A letter of declaration from marketing authorized holder that the specifications

of drug substance have not changed and the reproducibility of the process has not been affected

2. Comparative batch analysis data with specification and results (in a comparative tabulated format) on a minimum of one production or pilot batch manufactured to both the currently approved and proposed batch sizes. Batch data on the next two full production batches should be available on request or reported if outside specification (with proposed action).

3. Amended relevant ACTD Section S (where applicable).

MiV- PA 6

Change of in-process controls applied during the manufacture of the drug substance [including tightening and addition of new in-process test and where European Pharmacopoeial Certificate of Suitability (CEP) is not available]

C

1. In-process limits are tightened or addition of new tests. 2. The change is not a consequence of any commitment from previous

assessments to review specification limits. 3. The change does not result from unexpected events arising during

manufacture e.g. new unqualified impurity; change in total impurity limits. 4. Any new test method does not concern a novel non-standard technique or a

standard technique used in a novel way. 5. Refer to MiV-PA12 if this change resulted in revision of CEP.

D

1. A description of the analytical method and summary of validation data must be

provided for all new analytical methods (where applicable). 2. Comparative tabulated format of the proposed and current in-process controls

and the relevant changes. 3. Comparative batch analysis data of two production batches of the drug

substance for all tests in the proposed specification (where applicable).


20

MiV- PA7

Change of manufacturing process of the drug substance [where European Pharmacopoeial Certificate of Suitability (CEP) is not available]

C

1. No adverse change in qualitative and/or quantitative impurity profile which

would require further qualifications in safety studies. 2. The synthetic route remains the same (for example, intermediates remain the

same). 3. Manufacturing process of drug substance does not use any materials of

human/animal origin for which assessment is required of viral safety. 4. Physicochemical characteristics and other relevant properties of drug

substance remain unchanged. 5. Specifications and stability performance of drug substance remain unchanged. 6. Refer to MiV-PA12 if this change resulted in revision of CEP.

D

1. Drug Master File (DMF), or relevant updated drug substance (DS) section or

equivalent/audit document. 2. Comparative tabulated format of the currently approved and new processes

with changes highlighted (where available). 3. For sterile drug substance, process validation report (where applicable). 4. A letter of declaration from marketing authorization holder stating that no new

impurities have been introduced at or above the accepted threshold for qualification of impurities or that there is no increase in the levels of impurities, which require further safety studies.

5. A letter of declaration from the marketing authorization holder stating that the specifications of the drug substance have not changed or if there is any change to the specification ( for example, tightening), the texts of the currently approved and proposed specifications should be provided (in a comparative tabulated format where possible).

6. Certificate of analysis for two batches of the drug substance. 7. A declaration from the marketing authorization holder that the relevant stability

studies of the drug product in accordance with the ASEAN Guideline On Stability Study Of Drug Product have been started and that the relevant stability studies will be finalized; data should be provided only if outside specification (with proposed action).

8. Batch analysis data (in a comparative tabulated format) of drug product of at least two batches (pilot/production scale) manufactured with the drug substance according to the currently approved and proposed processes.


21

MiV- PA8

Change of the specification of drug substance a) Specification limits are tightened b) Addition of new test parameter and limits

C

1. This is only applicable for drug substances which are non-compendial and

generic drug substances without European Pharmacopoeial Certificate of Suitability (CEP)

2. The change should not be the result of unexpected events arising during manufacture or because of stability concerns.

3. Test procedures remain the same, or changes in the test procedure are minor. 4. For (b) - applicable to non-compendial method only. 5. Refer to MiV-PA12 if this change resulted in revision of CEP. 6. For widening of specification limits and deletion of test parameter and limits of

drug substance, please refer to MaV-6.

D

(a) Specification limits are tightened

1. Technical justification for the change. 2. Comparative tabulated format of the currently approved and revised

specification of drug substance with changes highlighted. 3. Comparative batch analysis data of the drug substance for all tests in the new

specification for two pilot or production scale batches. (b) Addition of new test parameter and limits In addition to the above documents,

4. Description of any new analytical method and summary of the validation data.

MiV- PA9

Change of the test procedure of non-compendial drug substance

C

1. Results of method validation show new test procedure to be at least equivalent

to the former procedure. 2. Refer to MiV-PA12 if this change resulted in revision of CEP.

D

1. Description of the analytical methodology, a summary of validation data, and

comparative analytical results between the currently approved and proposed test (where applicable).

2. Specification of the drug substance.


22

MiV- PA 10

Change of shelf-life or re-test period for drug substance

C

1. The stability studies must show compliance with specification. 2. No change in storage condition. 3. Refer to MiV-PA12 if this change resulted in revision of CEP.

D

1. Specifications of the drug substance. 2. Stability data of the drug substance should be presented on at least two pilot or

production scale batches of the requested shelf-life or retest period.

MiV- PA 11

Change of storage condition for drug substance

C

1. The stability studies must show compliance with specification. 2. No change in shelf-life/retest period. 3. Refer to MiV-PA12 if this change resulted in revision of CEP.

D

1. Specifications of the drug substance. 2. Stability data of the drug substance should be presented on at least two pilot or

production scale batches of the requested storage condition.

MiV- PA 12

Revision of European Pharmacopoeial Certificate of Suitability (CEP) of drug substance

C None

D


substance, latest version, with all annexes issued by EDQM. 2. If this change is due to drug substance specification change, a declaration

from the applicant that the relevant stability studies of the drug product in accordance with ASEAN Guideline On Stability Study Of Drug Product have been started and that the relevant stability studies will be finalized; data should be provided only if outside specification (with proposed action).

3. Specifications of drug substance (where applicable). 4. Results of batch analysis from the drug substance manufacturer*

demonstrating compliance with the Ph. Eur monograph and including additional test/limits listed on the CEP (where applicable).

5. Additional data to address any relevant parameter(s) not addressed in the CEP such as stability data (S7), if a re-test period is not stated on the CEP and physicochemical characteristics (e.g. particle size, polymorphism etc), if applicable.

* If the drug substance manufacturer is CEP certified and the drug product manufacturer claims otherwise (USP, JP, In-house etc), data covering S4.1 to S4.5 from the drug product manufacturer should be submitted.


23

MiV-PA13

Change of batch size of non-sterile drug product

C

1. The change does not affect consistency of production. 2. Process validation scheme and/or report is available or validation of the

manufacturing process has been successfully carried out according to protocol with at least three batches at the proposed new batch size in accordance with the ASEAN Guideline on Submission of Manufacturing Process Validation Data For Drug Registration.

3. Release and end-of-shelf-life specifications of drug product remain unchanged. 4. This is applicable to change of batch size up to 10-fold compared to the

currently registered batch size. 5. For change of batch size for sterile products, please refer to MaV-7 and for

change of batch size more than 10-fold compared to the currently registered batch size, please refer MaV-8.

D

1. Comparative tabulated format of proposed and current batch manufacturing

formula. 2. Validation scheme and/or report of the manufacturing process as per ASEAN

Guideline on Submission of Manufacturing Process Validation Data for Drug Registration appropriate to the proposed batch size should be provided upon submission.

3. Revised ACTD Section P3.1-3.4 (where applicable). 4. Release and shelf-life specifications of the drug product. 5. Batch analysis data (in a comparative table) of drug production a minimum of

one production batch according to currently approved and proposed batch sizes and a letter of undertaking to submit batch data on the next full production batch.


MiV-PA14

Reduction or removal of overage

C

1. Changes of previously approved manufacturing overages of drug substance

only. 2. Release and end-of-shelf-life specifications of drug product remain unchanged.

D

1. Justification for the change. 2. Comparative tabulated format of currently approved and proposed batch

manufacturing formula. 3. Certificate of analysis for two batches of the finished product. 4. Stability data as per ASEAN Guideline On Stability Study Of Drug Product and



24

MiV - PA15

Qualitative and/or quantitative change of excipient

a) For immediate release oral dosage forms (as per Level 1, Part III Components and Composition, SUPAC guideline)

b) For other non-critical dosage forms eg. oral liquid, external preparation.

C 1. Replacement of an excipient with a comparable excipient of the same

functional characteristics (where applicable). 2. The dissolution profile of the proposed product is comparable to that of the

current approved product. 3. Process validation scheme and/or report is available or validation of the

manufacturing process has been successfully carried out according to protocol with at least three batches of the proposed product formula in accordance with the ASEAN Guideline on Submission of Manufacturing Process Validation Data For Drug Registration.

4. Release and shelf-life specifications of the drug product remain unchanged 5. For qualitative or quantitative change of excipient for immediate release (Level

2 and 3 change as per SUPAC) and modified release oral dosage forms and other critical dosage forms, please refer to MaV-10.

D


variation (where applicable). 2. A declaration that the new excipient does not interfere with the drug product

release and shelf-life specifications test method (where applicable). 3. Justification for the change must be given by appropriate development of

pharmaceutics. 4. Comparative tabulated format of the current and revised product formulation

with calculated changes highlighted (please state changes in the percentage of the proposed excipient out of the total target dosage form weight, where applicable).

5. Comparative dissolution profile data of at least one representative pilot/production batch of the drug product between the currently approved and proposed solid dosage forms formulation.

6. Revised batch manufacturing formula. 7. Validation scheme and/or report of the manufacturing process as per ASEAN

Guideline on Submission of Manufacturing Process Validation Data for Drug Registration appropriate to the proposed change in product formula should be provided upon submission (where applicable).

8. Revised ACTD Section P3.1-3.4 (where applicable). 9. Specifications of the proposed excipient. 10. For proposed excipients made of ruminants source, Transmitting Animal

Spongiform Encephalopathy (TSE)-free certificate or Bovine Spongiform Encephalopathy (BSE)-free cert issued from relevant veterinary authority of the issuing country (where applicable).

11. Release and shelf-life specifications. 12. Batch analysis data (in a comparative tabulated format) of drug product of at

least two production (or one production batch and two pilot batches) according to currently approved and proposed product formula.


14. Justification for not submitting a new bioequivalence study according to the ASEAN Guidelines For The Conduct of Bioavailability and Bioequivalence Studies.


25

MiV - PA16

Quantitative change in coating weight of tablets or weight and/or size of capsule shell for immediate release oral solid dosage form

C

1. The dissolution profile of the proposed product is comparable to that of the

current approved product. 2. The product release and end-of-shelf-life specifications of the drug product

remain unchanged except for the weight and/or size. 3. For quantitative change in coating weight of tablets or weight and/or size of

capsule shell for modified release oral solid dosage forms please refer to MaV-11.

D

1. Revised draft of product label incorporating the proposed change (where

applicable). 2. A declaration from marketing authorization holder that the change does not

interfere with the drug product release and shelf-life specifications test method. 3. Comparative tabulated format of current and proposed product and batch

manufacturing formula. 4. Comparative dissolution profile data of at least one pilot/production batch of

the drug product between the currently approved and proposed composition. 5. Revised release and shelf-life specifications of the drug product. 6. Stability data as per ASEAN Guideline On Stability Study Of Drug Product and

report if any results fall outside shelf-life specifications (with proposed action). Except for the change in weight and/or size of capsule shell, a letter of declaration from the applicant that the relevant stability studies of the drug product in accordance with ASEAN Guideline on Stability Study of Drug Product have been started will suffice.

7. Justification for not submitting a new bioequivalence study according to the ASEAN Guidelines For The Conduct of Bioavailability and Bioequivalence Studies (where applicable).


26

MiV- PA17

Change of the colouring/flavouring agent of the product [addition, deletion or replacement of colourant(s)/flavour(s)]

C

1. Same functional characteristics, no change in dissolution profile for solid oral

dosage forms. 2. The proposed colouring/flavouring agents must not have been rejected for

pharmaceutical use. 3. The release and shelf-life specifications of the drug product remain unchanged

except for the change in colour/flavour.

D


variation (where applicable). 2. A declaration from marketing authorization holder that the change does not

interfere with the drug product release and shelf-life specifications test method. 3. A letter of commitment from product owner or marketing authorization holder to

inform users of the relevant change (where applicable). 4. Revised product formulation and batch manufacturing formula. 5. Qualitative and quantitative information of the current and proposed

colouring/flavouring agent in a comparative table. 6. For proposed excipients made of ruminants source, Transmitting Animal

Spongiform Encephalopathy (TSE)-free certificate or Bovine Spongiform Encephalopathy (BSE)-free certificate issued from relevant veterinary authority of the issuing country (where applicable).

7. Revised release and shelf-life specifications of the drug product. 8. Stability data as per ASEAN Guideline On Stability Study Of Drug Product and


MiV- PA18

Deletion of the solvent/diluent for the drug product

C

1. The proposed change does not result in any change in the dosage form,

regimen, indication, method of administration of the product.

D


variation (where applicable). 2. Justification for the deletion of the solvent/diluent, including a statement

regarding alternative means to obtain the solvent/diluent. 3. Amended relevant ACTD Section P (where applicable).


27

MiV-PA19

Change of in-process controls applied during the manufacture of the drug product (including tightening and addition of new in-process test)

C

1. Release and shelf-life specifications of drug product remain unchanged. 2. The change is not a consequence of any commitment from previous

assessments to review specification limits. 3. The change does not result from unexpected events arising during

manufacture e.g. new unqualified impurity; change in total impurity limits. 4. Any new test method does not concern a novel non-standard technique or a

standard technique used in a novel way.

D

1. Comparative tabulated format of currently approved and proposed in-process

controls. 2. A description of the analytical methodology and summary of validation data

must be provided for all new analytical methods (where applicable). 3. Revised in-process specifications together with justification and relevant

process validation data. 4. Comparative batch analysis data of drug product of at least two

production/pilot batches.


28

MiV- PA20

Minor change of the manufacturing process for non-sterile product

C

1. The same currently approved manufacturing site. 2. The overall manufacturing principle remains the same. 3. The change does not cause negative impact on the quality, safety and efficacy

of the drug product. 4. The dissolution profile of the proposed product is comparable to that of the

current approved product. 5. Release and end-of-shelf-life specifications of drug product remain unchanged. 6. For major change in the manufacturing process for drug product, please refer

to MaV-9.

D

1. For solid oral dosage forms, comparative dissolution profile data of at least one

representative production batch of the drug product between the currently approved and proposed solid oral dosage forms formulation.

2. Description of the new manufacturing process and technical justification for the change.

3. Comparative tabulated format of present and proposed process with changes highlighted.

4. For semi solid and suspension products, validation scheme and/or report of the manufacturing process as per ASEAN Guideline on Submission of Manufacturing Process Validation Data for Drug Registration should be provided upon submission.

5. Copy of currently approved release and shelf-life specifications. Or, alternately, copy of revised release and shelf-life specifications that supports that the new process must lead to an identical or better product regarding all aspects of quality, safety and efficacy.

6. Batch analysis data (in a comparative tabulated format) of drug product on a minimum of one batch manufactured to both the currently approved and the proposed process; batch data on the next two full production batches should be made available upon request.

7. A declaration from the marketing authorization holder that the relevant stability studies of the drug product in accordance with the ASEAN Guideline on Stability Study of Drug Product have been started and that the relevant stability studies will be finalized; data should be provided only if outside specification (with proposed action).”

8. Justification for not submitting a new bioequivalence study according to the current Bioavailability and Bioequivalence guidance (where applicable).


29

MiV-PA21

Change of specifications of an excipient a) Specification limits are tightened b) Addition of new test parameter and limits

C

1. Release and end-of-shelf-life specifications of drug product remain unchanged. 2. The change should not be the result of unexpected events arising during

manufacture or because of stability concerns. 3. Applicable to non compendial excipients. For compendial excipients, please

refer to MiV-N9.

D

1. Description of new method and summary of analytical validation (applicable for

addition of new parameter). 2. Comparative tabulated format of the current and revised specification of the

excipient with changes highlighted. 3. Batch analysis data of the excipient for all tests in the new specification.

MiV-PA22

Change of a test procedure for an excipient, including replacement of an approved test procedure by a new test procedure

C

1. Appropriate method validation studies have been performed in accordance

with the ASEAN Guidelines For Validation of Analytical Procedures. 2. Results of method validation show new test procedure to be at least equivalent

to the former procedure. 3. There have been no changes of the total impurity limits. 4. Only applicable to the currently approved test parameters. 5. No new unqualified impurities are detected. 6. This applies for non-compendial excipient.

D

1. Description of the analytical methodology with a comparative tabulation of the

changes. 2. For quantitative test change, comparative analytical validation results showing

that the current and proposed tests are equivalent.


30

MiV-PA23

Change in the source of empty hard capsule

C

1. From TSE-risk material to vegetable-sourced or synthetic empty hard capsules

or vice versa. 2. No change in the formulation and manufacturing process of drug product. 3. Not applicable to change from hard capsule to soft gel. 4. Excipient and finished product release and end of shelf-life specifications

remain unchanged.

D

1. A letter of declaration from the manufacturer or the marketing authorization

holder of the material that it is purely of vegetable, animal or synthetic origin. 2. Technical specifications and composition of the empty hard capsule of the new

source. 3. For empty hard capsule made of ruminants source, Transmitting Animal

Spongiform Encephalopathy (TSE)-free certificate or Bovine Spongiform Encephalopathy (BSE)-free cert issued by a competent authority of the issuing country.

4. Comparative dissolution profile data of one batch representative of pilot/production batch of the drug product using hard capsule between the two sources (where applicable).

5. Certificate of Analysis of the empty hard capsule of the proposed new source. 6. Stability data as per ASEAN Guideline On Stability Study Of Drug Product and


MiV-PA24

Change of release and shelf-life specifications of the drug product a) Specification limits are tightened b) Addition of new test parameter and limits

C

1. Applicable to non-compendial method. 2. The change should not be the result of unexpected events arising during

manufacture or because of stability concerns. 3. The test methods remain the same or changes in the test methods are minor. 4. If there are changes to the test procedure, MiV-PA27 is also applicable. 5. For widening of specification limits and deletion of test parameter and limits of

drug product, please refer to MaV-6.

D

(a) Specification limits are tightened

1. Technical justification for the change. 2. Comparative tabulated format of the current and revised release and shelf-life

specifications of the drug product with changes highlighted. 3. Comparative batch analysis of the drug product for all tests in the new

specification of at least two batches. (b) Addition of new test parameter and limits In addition to the above documents:

4. Description of any new method and summary of analytical validation data for non-compendial method.

5. Stability data as per ASEAN Guideline On Stability Study Of Drug Product and report if any results fall outside shelf-life specifications (with proposed action). (where applicable).


31

MiV-PA25

Change of imprints, bossing or other markings on tablets or printing on capsules including addition or change of inks used for product marking

C

(a) Except score/break-line

1. New markings do not cause confusion with other registered products. 2. Any ink proposed must comply to relevant pharmaceutical legislation or of food

grade and not a listed banned substance. 3. Release and shelf-life specifications of the drug product remain unchanged

except for appearance. (b) On score/break-line In addition to the above conditions,

4. Score/break-line is not meant for cosmetic purpose. 5. Applicable to addition or removal of score/break-line.

D

(a) Except score/break-line

1. Revised drafts of the package insert and labeling incorporating the proposed variation (where applicable).

2. A letter of commitment from product owner or marketing authorization holder to inform users of the relevant change (where applicable).

3. Details and specifications of the proposed new inks (where applicable). 4. Detailed drawing or written description of the current and proposed

imprint/bossing/markings. 5. Certificate of analysis of ink/printing material (pharmaceutical grade and of

food grade) (where applicable). 6. Release and shelf-life specifications of the drug product with the new product

description. (b) On score/break-line In addition to the above documents,

7. Justification for the change (i.e. change in dosing regimen). 8. Data on test of content uniformity of the subdivided parts of the tablets at

release should be submitted. 9. Certificate of analysis of two production/pilot scale batches.


32

MiV- PA26

Change of dimensions and/or shape of tablets, capsules, suppositories or pessaries without change in qualitative and quantitative composition and mean mass a) Immediate release oral solid dosage form, suppositories and pessaries b) Other than immediate release oral solid dosage forms, suppositories and pessaries.

C

1. If appropriate, the dissolution profile of the proposed product is comparable to

that of the current approved product. 2. Release and shelf-life specifications of the drug product remain unchanged

except for dimension and/or shape.

D

(a) Immediate release oral solid dosage form, suppositories and pessaries

1. Revised drafts of the package insert and labeling incorporating the proposed variation (where applicable).

2. Detailed drawing or written description of the current and proposed appearance.

3. Comparative dissolution data on at least one pilot/production batch of the currently approved and proposed dimensions.

4. Data on test of content uniformity of the subdivided parts of tablets at release as conformed to compendial requirement should be submitted (only applicable for drug product with score/break-line).

5. Release and shelf-life specifications of the drug product. (b) Other than immediate release oral solid dosage forms, suppositories and pessaries In addition to the above condition,

6. Justification for not submitting a new bioequivalence study according to the ASEAN Guidelines For The Conduct of Bioavailability and Bioequivalence Studies (where applicable).


33

MiV-PA27

Change in the test procedure of the drug product (including replacement or addition of a test procedure)

C

1. Drug product specifications are not adversely affected unless the specifications

are tightened. 2. Results of method verification/validation show new test procedure to be at

least equivalent to the former procedure. 3. The change should not be the result of unexpected events arising during

manufacture or because of stability concerns.

D

1. Justification for the proposed change. 2. Comparative tabulated format of the currently approved and proposed release

and shelf-life specifications of the drug product. 3. Description of the analytical methodology. 4. Appropriate verification/validation data and comparative analytical results

between the currently approved and proposed test. 5. Certificate of analysis of the finished product of two production batches when

made available.

MiV-PA28

Change in primary packaging material for non-sterile product a) Qualitative and quantitative composition and/or b) Type of container and/or c) Inclusion of primary packaging material

C

1. The proposed packaging material must be at least equivalent to or better than

the approved material in respect of its relevant properties. 2. The change only concerns the same packaging type (for example from blister

to blister). 3. Release and end-of-shelf-life specifications of drug product remain unchanged. 4. For change in the primary packaging material for sterile drug product, please

refer to MaV-12.

D

1. Revised drafts of the package insert incorporating the proposed variation

(where applicable). 2. Justification for the change in packaging material and appropriate scientific

studies on the new packaging. 3. For semi-solid and liquid dosage forms, proof must be provided that no

interaction between the content and the packaging material occurs (e.g. no migration of components of the proposed material into the content and no loss of components of the product into the pack).

4. Comparative tabulated format of the currently approved and proposed specifications of the primary packaging material (where applicable).



34

MiV- PA 29

Addition or replacement of a manufacturer for secondary packaging

C

None

D


variation (where applicable). 2. Proof that the proposed site is appropriately authorized (accredited by the

authority) for the packaging activity concerned such as a valid GMP certificate and/or CPP which covers the GMP certification.

3. Official letter from product owner authorizing the new manufacture or packager to perform secondary packaging (where applicable).

MiV-PA30

Change of pack size/fill volume and/or change of shape or dimension of container or closure for non-sterile product

C

1. The change only concerns the same packaging type and material. 2. The new size is consistent with the dosage regimen and duration of use as

approved in the package insert. 3. Change in the dimension of the primary packaging material (where applicable). 4. Release and shelf-life specifications of the drug product remain unchanged. 5. For change of pack size/fill volume and/or change of shape or dimension of

container or closure for sterile solid and liquid drug product, please refer to MaV-13.

D


variation (where applicable). 2. Justification for the proposed pack size. 3. A declaration from the marketing authorization holder that the relevant stability

studies of the drug product in accordance with the ASEAN Guideline on Stability Study of Drug Product have been started and that the relevant stability studies will be finalized; data should be provided only if outside specification (with proposed action).


35

MiV- PA31

Change of outer carton pack sizes for a drug product

C

1. Primary packaging materials remain unchanged. 2. No other changes except for the change of outer carton pack sizes for a drug

product. 3. The remaining pack sizes are adequate to accommodate the dosing regimen

as per the approved product labeling.

D


variation (where applicable). 2. Letter of declaration from the marketing authorization holder stating that no

other changes except for the change of outer carton pack sizes for a drug product.

MiV- PA 32

Change in any part of the (primary) packaging material not in contact with the finished product formulation such as colour of flip-off caps, colour code rings on ampoules, change of needle shield (different plastic used)

C

1. The change does not concern a part of the packaging material, which affects

the delivery, use, safety or stability of the finished product.

D

1. Amendment of the relevant section(s) of the dossier (presented in the ACTD

format), including revised product labeling as appropriate.

MiV-PA33

Addition or replacement of measuring device for oral liquid dosage forms and other dosage form

C

1. The size and where applicable, the accuracy of the proposed measuring

device must be compatible with the approved posology. 2. The new device is compatible with the drug product.

D

1. Revised draft of the package insert and labeling incorporating the proposed

variation (where applicable). 2. Description of the device (including a drawing; where applicable). 3. The composition of the device material. Where applicable the materials should

comply with the pharmacopoeia. 4. Justification that size and accuracy of the device are adequate for the posology

as approved in the product labeling.


36

MiV-PA34

Reduction of shelf-life of the drug product a) As a package for sale and/or b) After first opening and/or c) After dilution/reconstitution

C



life specification for the reconstituted product. 3. For extension of shelf-life, please refer to MaV-15.

D


variation (where applicable). 2. Justification letter for the change of shelf-life of the drug product (where

applicable). 3. A letter of commitment from product owner or marketing authorization holder to

inform users of the relevant change (where applicable). 4. Results of appropriate real time stability studies covering the duration of

proposed shelf-life of at least two pilot/production scale batches of the product in the authorized packaging material

a) as a package for sale and/or b) after first opening and/or c) after the dilution/reconstitution

in accordance with the ASEAN Guidelines on Stability Study of Drug Product; results of appropriate microbiological testing should be included (where appropriate).

MiV-PA35

Change of storage conditions of the drug product (Increasing from the current approved storage condition)

a) As a package for sale and/or b) After first opening and/or c) After dilution/reconstitution

C



life specification for the reconstituted product. 3. For change of storage condition (lowering from the current approved storage

condition), please refer to MaV-16.

D


variation (where applicable). 2. Technical justification for the change of storage condition. 3. Results of appropriate real time stability studies covering the duration of

currently approved shelf-life (at proposed storage condition) of at least two pilot/production scale batches of the product and in the authorized packaging material in accordance with the ASEAN Guidelines on Stability Study of Drug Product.


37

9. MINOR VARIATION NOTIFICATION

Minor Variation (MiV-N)

Notification

MiV-N1 Change in name and/or address (for example: postal code, street name) of the marketing authorization holder [Note: The Drug Regulatory Authority reserves the right to re-categorize this variation as MiV-PA, if deemed necessary]

C

1. The name change refers to the renaming of a company or organization. 2. The change does not include transfer of marketing authorization to another

company. 3. For change on the part of marketing authorization holder in product labelling

only. Please refer to MaV-2 and MiV-PA2 if other parts are involved.

D

1. Revised draft package insert and labeling incorporating the proposed variation

(where applicable). 2. Letter by the product owner authorizing the new name of marketing

authorization holder to hold the product license. 3. Official document from the relevant authority confirming the change with the

new name and/or address.

MiV- N2 Change of product owner

C

1. The marketing authorization holder remains the same. 2. The manufacturing site remains the same.

D


variation (where applicable). 2. Declaration on the transfer of ownership between old product owner and new

owner. 3. Official letter from the new product owner declaring the change, and

authorizing the local license holder to be responsible for the product license. 4. If the new product owner is not the manufacturer of the drug product, an official

letter by the new product owner authorizing the manufacturer to manufacture the drug product on its behalf.

5. If the new product owner is not the manufacturer of the drug product, letter of acceptance from the manufacturer that it will be held responsible for manufacturing and ensuring the efficacy, quality and safety aspect of the drug product.


38

MiV- N3 Change in ownership of manufacturer [Note: The Drug Regulatory Authority reserves the right to re-categorize this variation as MiV-PA, if deemed necessary]

C

1. The manufacturing site remains unchanged. 2. No other changes except for the change in ownership of manufacturer.

D


variation (where applicable). 2. Letter of justification on the transfer of ownership such as a valid GMP

certificate. 3. Official letter stating the transfer of ownership from old manufacturer to new

manufacturer (where applicable). 4. In case of a contract manufacturer, official letter from product owner declaring

the change and authorizing the new manufacturer to manufacture the drug products on its behalf.

5. In case of a contract manufacturer, letter of acceptance from the new manufacturer that it will be held responsible for manufacturing and ensuring the efficacy, quality and safety aspect of the drug product.

MiV- N4 Change of the name or address (for example: postal code, street name) of the manufacturer of drug product [Note: The Drug Regulatory Authority reserves the right to re-categorize this variation as MiV-PA, if deemed necessary]

C

1. The manufacturing site remains the same. 2. No other changes except for the change of the name and/or address of a

manufacturer of the drug product. 3. Not applicable to the case in which it involves change in ownership of the

manufacturer. For change in ownership of manufacturer, please refer MiV-N3.

D


variation (where applicable). 2. A valid GMP certificate, CPP which covers the GMP certification or official

document from relevant authority confirming the new name and/or address. 3. Official letter from product owner authorizing the manufacturer with new

name/address to manufacture the drug product.


39

MiV- N5 Change of the name or address (for example: postal code, street name) of the company or manufacturer responsible for batch release [Note: The Drug Regulatory Authority reserves the right to re-categorize this variation as MiV-PA, if deemed necessary]

C

1. The manufacturer of the drug product remains the same. 2. The batch release site remains the same. 3. Not applicable to the case in which it involves change in ownership of the

manufacturer. For change in ownership of manufacturer, please refer MiV-N3.

D


variation (where applicable). 2. A valid GMP certificate CPP which covers the GMP certification or official

document from relevant authority confirming the new name or address (where applicable).

3. Official letter from product owner authorizing company/manufacturer with new name/address responsible for batch release.

4. A declaration from the marketing authorization holder that the change does not involve change of batch release site.

MiV- N6 Change of the name and/or address (for example: postal code, street name) of a manufacturer of the drug substance

C

1. The manufacturing site of the drug substance remains unchanged. 2. No other changes except for the change of the name and/or address of a

manufacturer of the drug substance.

D

1. Updated information of the manufacturer of the drug substance. 2. Official document/evidence when required.

MiV- N7 Withdrawal/deletion of the alternative manufacturer(s) (for drug substance and/or drug product and/or packager)

C

1. An alternative manufacturer is registered.

D

1. Reason for withdrawal/deletion.


40

MiV-N8 Renewal of European Pharmacopoeial Certificate of Suitability (CEP)

C

1. Only applicable if the renewal of CEP does not involve any variation.

D


substance, latest version, with all annexes issued by EDQM.

MiV-N9 Change of release and shelf-life specifications of the drug product and/or drug substance and/or excipient, following the updates in the compendium

C

1. Applicable to compendial specifications only. 2. Change is made exclusively to comply with an update of the relevant

monograph of the compendium.

D

1. Revised release and shelf-life specifications. 2. Tabulation of the current and revised release and shelf-life specifications of the

drug product with changes highlighted. 3. Batch analysis of the drug product for all tests in the new specification of at

least two batches.

MiV-N10 Deletion of pack size for a product

C

1. The remaining pack sizes are adequate to accommodate the dosing regimen

as per the approved product labeling. 2. For addition of pack size for sterile and non-sterile products, please refer to

MaV-13 and MiV-PA30 respectively. For change in the outer carton pack size, please refer to MiV-PA31.

D


variation (where applicable). 2. Reason for deletion.


41

10. GLOSSARY Refer to ACTD/ACTR Glossary 11. REFERENCES

1. European Medicine Agency Variation Guideline, 2008

2. Communication from the Commission — Guideline on the details of the various

categories of variations to the terms of marketing authorisations for medicinal

products for human use and veterinary medicinal products - Official Journal of

the European Union (C 17/1 of 22.01.2010)

3. Commission Regulation (EC) No 1234/2008 Official Journal of the European

Union (L334 of 12 December 2008)

4. WHO Guidance on Variations To A Prequalified Product Dossier, 2007

5. SUPAC Guideline Immediate Release Solid Oral Dosage Forms, Scale-up and

Post-approval Changes: Chemistry, Manufacturing and Controls, In Vitro

Dissolution Testing and In Vivo Bioequivalence Documentation, November

1995

6. SUPAC-MR: Modified Release Solid, Oral Dosage Forms, Scale-Up and Post -

approval Changes: Chemistry, Manufacturing, and Controls; In Vitro

Dissolution Testing and In Vivo Bioequivalence Documentation, September

1997

7. WHO Technical Report Series, No. 953, 2009

8. WHO Quality Assurance of Pharmaceuticals – A Compendium of Guidelines

and Related Materials – Volume 1

9. ASEAN Guideline on Stability Study of Drug Product, 22 February 2005

10. ASEAN Guideline on Submission of Manufacturing Process Validation Data for

Drug Registration

11. ASEAN Guideline for Validation of Analytical Procedures

12. ASEAN Guideline for the Conduct of Bioavailability and Bioequivalence Studies,

21 July 2004